- Prof. Birandra K. Sinha
- Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at National Institutes of Environmental Health Sciences/NIH, North Carolina, NC, USA.
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Special Issue Introduction
The development of multidrug resistance to cancer chemotherapy is a major problem for the effective treatment of human malignancies in the clinic. One of the main reasons for this drug resistance involves the overexpression of various ABC transporters, e.g., P-glycoprotein 170, BCRP and MRP’s. These transporter proteins use ATP to remove anticancer drugs from their cellular targets, reducing drug concentration, and leading to a poor treatment outcome and survival. Various anticancer drugs (e.g., adriamycin, topotecan, etc.) form reactive free radical species which generate oxygen-derived reactive species (ROS), hydrogen peroxide (H2O2), hydroxyl radical (•OH), superoxide anion radical (O2.−) and singlet oxygen (1O2). Under normal cellular conditions, cellular redox homeostasis is maintained as a result of the balance between cellular oxidants and antioxidants. Excessive levels of cellular ROS induce oxidative stress that leads to various pathological states, including cancer. Furthermore, when ROS concentrations become extremely high, they induce cellular damage, causing cell death. ROS are implicated in the mechanism of tumor cell death by certain anticancer drugs. Tumor cells can overcome drug-induced oxidative stress by enhancing their antioxidant systems, leading to a new redox balance with a higher tolerance to ROS level, a process known as ‘Redox Resetting’. Such drug-induced redox resetting has recently been shown to result in the failure to kill tumor cells or emergence of drug resistance. Research shows that drug-induced redox signaling leads to changes in expression and/or activity of ABC transporters. These include conformational changes of transporters, and regulation of the expression of transporters at transcriptional and gene amplifications. While a clear picture is emerging on the roles of oxidative stress in cancer, much work is needed to understand how these events lead to multidrug resistance, especially in vivo. Furthermore, we must understand how this knowledge can be applied in the clinic for the treatment of multidrug tumors and emerging drug-derived cancer stem cells. Here, we summarize our current understanding of oxidative stress, its relationship to cancer drug resistance and the future prospect in a clinical setting.
Submission Deadline30 Jun 2021